2 L, and heptane (5 L) was added. The batch was allowed to
cool to RT, aged for 1 h, and the slurry was filtered. The filter
cake was washed with heptane (1 L), and the resulting solid
was dried under a stream of nitrogen to afford 626 g of 8 (99.6
LCAP, 81% isolated yield). mp 94.1-95.1 °C; IR (film) 3393,
3297, 3195, 1677, 1613, 1562, 1485, 1383, 1332, 1287, 1115
cm-1; 1H NMR (400 MHz, CDCl3) 8.44 (s, 1H), 7.81 (d, 1H,
J ) 8.7 Hz), 6.86 (d, 1H, J ) 8.8 Hz), 5.96 (br s, 1H), 5.53 (br
s, 1H), 1.75 (s, 6 H); 13C NMR (400 MHz, CDCl3) δ 176.8,
163.9, 144.6, 136.0, 127.9, 125.2, 122.5, 121.2, 120.9, 120.6,
120.2, 119.8, 112.3,81.6, 25.0; Anal. Calcd for C10H11F3N2O2:
C, 48.39; H, 4.47; N, 11.29; Found: C, 48.33; H, 4.17; N, 11.18.
(N-[(1Z)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-meth-
ylprop-1-en-1-yl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-
yl]oxy}propanamide (6). A three-neck, 5 L round-bottom flask
fitted with a mechanical stirrer, reflux condenser, and a nitrogen
inlet was charged with Pd2dba3 (27.5 g, 30 mmol), dppb (51.2
g, 120 mmol), 12 (526 g, 1.2 mol), 8 (313 g, 1.26 mol), and
potassium carbonate (332 g, 2.4 mol). The flask was evacuated
and backfilled with nitrogen three times, and then charged with
tert-amyl alcohol (2.4 L, purged with nitrogen gas for 2 h).
The flask was heated to 100 °C and stirred for 18 h. The
resulting suspension was cooled to 25 °C, diluted with 7.2 L
of MTBE, charged with Darco KB-B (250 g), and stirred for
2 h at RT. The batch was filtered over a pad of Solka-Floc,
and the filter cake was washed with 7 L of MTBE. The batch
was concentrated under vacuum at 40 °C to a volume of 1.5 L,
and heptane (5 L) was added over 30 min. The batch was cooled
to 20 °C and filtered. The filter cake was washed with 2 L of
heptane/MTBE (10:1) and dried under a stream of nitrogen to
provide 553 g of 6 (98.4 LCAP, 87% isolated yield). Mp
126.5-127.5 °C; IR (film) 3400, 3323, 3061, 2985, 2934, 2226,
the solvent switch, 500 mL of heptane was added, and the
mixture was cooled to 20 °C. The batch was aged for 30 min,
then filtered and washed with 1 L of toluene. The resulting solid
was dried overnight under a stream of nitrogen to afford 522 g
of 15 (99.4 LCAP, 94% isolated yield). mp 153.7-154.5 °C;
IR (film) 3393, 3323, 3195, 2985, 2934, 2245, 1658, 1619,
1
1492, 1383, 1326, 1288, 1147, 1122, 1071, 1013 cm-1; H
NMR (400 MHz, CDCl3) 8.32 (m, 1H), 7.70 (dd, 1H, J ) 9.0,
2.9 Hz), 7.58 (dt, 1H, J ) 7.9, 1.5 Hz), 7.43 (t, 1H, J ) 1.7
Hz), 7.15 (m, 4H), 7.02 (dt, 1H, J ) 7.6, 1.4 Hz), 6.98 (m,
2H), 6.52 (d, 1H, J ) 8.5 Hz), 6.10 (br s, 1H), 3.67 (s, 2H),
2.31 (s, 3H), 1.53 (s, 6H); 13C NMR (400 MHz, CDCl3) δ 172.0,
168.8, 163.5, 144.36, 144.33, 144.29, 144.25, 140.3, 137.1,
136.09, 136.06, 136.03, 136.00, 133.7, 132.4, 132.1, 130.7,
129.9, 128.8, 128.6, 127.9, 127.5, 126.7, 126.1, 125.2, 122.5,
121.3, 121.0, 120.6, 120.3, 119.8, 112.4, 82.0, 38.5, 24.7, 16.5;
Anal. Calcd for C27H25ClF3N3O3: C, 60.96; H, 4.74; N, 7.90;
Found: C, 60.94; H, 4.74; N, 7.83.
3-{(1S,2S)-1-(4-Chlorobenzyl)-2-[(2-methyl-2-{[5-(trifluo-
romethyl)pyridin-2-yl]oxy}propanoyl)amino]propyl}benzamide
(18). Catalyst Preparation. In
a N2-filled glovebox,
NBD2RhBF4 (105.5 mg, 0.28 mmol) and ligand 17 (170.5 mg,
0.30 mmol) were added to a 125 mL bottle and dissolved in
91 mL of degassed trifluoroethanol (TFE) with stirring at room
temperature for 25 min. A partial quantity of the resulting
solution, 86.5 mL, was added to a nitrogen-purged charging
apparatus, and 46 mL of TFE was added to the rinse chamber
of the charging apparatus. The complete charging apparatus was
sealed and removed from the glovebox.
Hydrogenation. Substrate 15 (115 g, 216 mmol) was
dissolved in 337 mL of TFE at room temperature and then was
charged to a 1 L autoclave. An additional 100 mL of TFE was
used to rinse the substrate solution bottle, and the combined
solution was degassed three times with nitrogen. The catalyst
was added via the charging apparatus connected to the autoclave
and rinsed with the TFE in the rinse chamber. The reaction
was heated to 40 °C, and pressure purged with hydrogen twice,
followed by hydrogen introduction to 150 psi. The reaction was
allowed to proceed for 17 h. The solution was cooled to room
temperature, solvent switched to isopropyl acetate (∼1.3 L,
containing 2.6% TFE), treated with Ecosorb C-941 (36 g), and
aged for 16 h at 40 °C. The slurry was filtered over a bed of
Solka-Floc and rinsed with IPAc (630 mL). The combined
filtrate was concentrated to 850 mL, heated to 65 °C, and
charged with n-heptane (490 mL). The solution was cooled to
45 °C, seeded with authentic 18 (1 g), and aged for 4 h at 45
°C. Additional n-heptane (2.7 L) was added over 15 h, the
mixture was filtered at 45 °C, and the cake was washed with
600 mL of n-heptane at room temperature. The resulting solid
was dried under vacuum to deliver 18 (106 g, 99.5% ee, 92%
yield). Mp 154-155 °C; [R23D] +98.7 (c ) 0.0069 g/mL,
CH2Cl2); IR (film) 3417, 3317, 3202, 2978, 2934, 1658, 1607,
1
1683, 1607, 1568, 1485, 1326, 1286, 1128, 1070 cm-1; H
NMR (400 MHz, CDCl3) δ 8.33 (m, 1H), 7.75 (dd, 1H, J )
8.6, 2.5 Hz), 7.39 (dt, 1H, J ) 7.6, 1.3 Hz), 7.25 (t, 1H, J )
1.7 Hz), 7.18 (m, 3H), 7.12 (dt, 1H, J ) 7.8, 1.5 Hz), 6.98 (d,
2H, 8.4 Hz), 6.62 (d, 1H, J ) 8.4 Hz), 3.66 (s, 2H), 2.28 (s,
3H), 1.54 (s, 6H); 13C NMR (400 MHz, CDCl3) δ 171.9, 163.5,
144.4, 141.3, 136.6, 136.2, 133.3, 132.3, 132.0, 131.5, 130.7,
129.7, 129.3, 128.7, 127.8, 126.4, 125.1, 122.4, 121.5, 121.1,
120.8, 120.5, 119.7, 118.3, 112.7, 112.4, 82.0, 38.4, 24.7, 16.7;
Anal. Calcd for C27H23ClF3N3O2: C, 63.10; H, 4.51; N, 8.18;
Found: C, 63.20; H, 4.29; N, 8.02.
3-{(1Z)-1-(4-Chlorobenzyl)-2-[(2-methyl-2-{[5-(trifluo-
romethyl)pyridin-2-yl]oxy}propanoyl)amino]prop-1-en-1-
yl}benzamide (15). A 5 L, 3-necked round-bottom flask
equipped with overhead stirrer, thermocouple, and nitrogen inlet
was charged with DMSO (2.7 L), 6 (524 g, 1.02 mol), and
K2CO3 (112 g, 0.810 mol). Hydrogen peroxide (30% aqueous
solution, 165 mL, 1.76 mol) was slowly added such that the
temperature never rose above 25 °C. The reaction was aged
for 1 h and then diluted with 1 L of isopropyl acetate and filtered
over a bed of Solka-Floc. The bed was washed with 4.5 L of
isopropyl acetate, and the resulting solution was washed with
5.5 L of water. The layers were separated, and the organic layer
was washed twice with 3.1 L of water. The resulting organic
layer was concentrated to a volume of 5 L, and then the solvent
was switched to 5 L of toluene at 60 °C. Upon completion of
1
1524, 1492, 1396, 1326, 1288, 1141, 1122, 1077 cm-1; H
NMR (400 MHz, CDCl3) 8.33 (m, 1H), 7.80 (dd, 1H, J ) 8.7,
2.6 Hz), 7.60 (m, 2H), 7.25 (dd, 1H, J ) 15.4, 5.1 Hz), 7.10
(m, 1H), 7.02 (m, 2H), 6.85 (d, 1H, J ) 8.5 Hz), 6.71 (m, 2H),
6.42 (br s, 1H), 6.22 (br s, 1H), 5.97 (d, 1H, J ) 9.1 Hz), 4.38
(m, 1H), 3.07 (m, 1H), 2.82 (m, 2H), 1.75 (s, 3H), 1.71 (s,
Vol. 13, No. 1, 2009 / Organic Process Research & Development
•
89